Genetic tools are enabling the molecular dissection of the functions and mechanisms of many biological processes. Transgenic manipulations provide powerful tools with which to test hypotheses regarding functions of specific cell types and molecules in vivo in combination with different types of experimental models. Various techniques are available that can target genetic manipulations specifically to astrocytes and that are enabling the molecular dissection of astrocyte biology in vivo. This article summarizes procedures and experience from our laboratory using transgenic strategies that enable either the ablation of proliferating astrocytes and related cells, or the deletion of specific molecules selectively from astrocytes, to study the functions of astrocytes and related cell types in health and disease in vivo using different experimental mouse models.